Chimeric mouse model for MRI contrast agent evaluation
Chimeric mouse model for MRI contrast agent evaluation
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DOI：
10.1002/mrm.27730
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发表时间：
2019-07-01
影响因子：
3.3
通讯作者：
Shapiro, Erik M.
中科院分区：
文献类型：
--
作者：
Mir, Faryal F.;Tomaszewski, Ryan P.;Shapiro, Erik M.
目的：虽然啮齿动物是评价造影剂的主要动物模型，但啮齿动物可能会歪曲新开发的造影剂对人体器官的清除。例如，Gd-BOPTA在啮齿类动物中的肝脏清除率类似于50%，但在人类中类似于5%。这项研究证明了表达人肝OATPs(有机阴离子转运多肽)的嵌合小鼠对临床使用的新型造影剂的评价是有益的。方法：对FVB(野生型)和OATP1B1/1B3敲入小鼠分别注射肝脏特异性磁共振造影剂(Gd-EOB-DTPA、Gd-BOPTA)和非特异性Gd-DTPA。对静脉注射的小鼠进行T1加权动态增强MRI检查。每个时间点计算肝脏MRI信号增强程度。还测量了每个时间点的Gd清除量和通过粪便和尿液排出的百分比。结果：在OATP1B1/1B3嵌合小鼠静脉注射Gd-BOPTA后，肝脏MRI信号的增强和消除比野生型小鼠更能反映人类肝脏的清除情况。与野生型小鼠相比，Gd-BOPTA肝脏MRI信号增强幅度降低至22%。野生型小鼠对Gd-BOPTA的排泄率为83%，而嵌合型小鼠的排泄率为32%。Gd-EOB-DTPA和Gd-DTPA的肝脏MRI信号增强和消除在野生型和嵌合型队列中相似。结论：Gd-EOB-DTPA、Gd-BOPTA和Gd-DTPA在OATP1B1/1B3嵌合基因敲除小鼠肝脏中的增强和消除与人类相似。这项研究提供的证据表明，与传统使用的野生型模型相比，嵌合敲入小鼠是用于临床的新型MRI造影剂的更有用的筛选工具。
Purpose: While rodents are the primary animal models for contrast agent evaluation, rodents can potentially misrepresent human organ clearance of newly developed contrast agents. For example, gadolinium (Gd)- BOPTA has similar to 50% hepatic clearance in rodents, but similar to 5% in humans. This study demonstrates the benefit of chimeric mice expressing human hepatic OATPs (organic anion- transporting polypeptides) to improve evaluation of novel contrast agents for clinical use. Methods: FVB (wild- type) and OATP1B1/1B3 knock- in mice were injected with hepatospecific MRI contrast agents (Gd- EOB- DTPA, Gd- BOPTA) and nonspecific Gd- DTPA. T1- weighted dynamic contrast- enhanced MRI was performed on mice injected intravenously. Hepatic MRI signal enhancement was calculated per time point. Mass of gadolinium cleared per time point and percentage elimination by means of feces and urine were also measured. Results: Following intravenous injection of Gd- BOPTA in chimeric OATP1B1/1B3 knock- in mice, hepatic MRI signal enhancement and elimination by liver was more reflective of human hepatic clearance than that measured in wild- type mice. Gd- BOPTA hepatic MRI signal enhancement was reduced to 22% relative to wildtype mice. Gd- BOPTA elimination in wild- type mice was 83% fecal compared with 32% fecal in chimeric mice. Hepatic MRI signal enhancement and elimination for Gd- EOB- DTPA and Gd- DTPA were similar between wild- type and chimeric cohorts. Conclusion: Hepatic MRI signal enhancement and elimination of Gd- EOB- DTPA, Gd- BOPTA, and Gd- DTPA in chimeric OATP1B1/1B3 knock- in mice closely mimics that seen in humans. This study provides evidence that the chimeric knock- in mouse is a more useful screening tool for novel MRI contrast agents destined for clinical use as compared to the traditionally used wild- type models.